DESCRIPTION: Tuberculosis is the leading cause of death in HIV-infected individuals in the world. Infection with HIV results in defects in cell mediated immunity that increases the severity of tuberculosis following infection, reinfection or reactivation of latent infection by Mycobacterium tuberculosis. This application for an R03 grant proposes to develop the immunomodulatory glycolipid a-galactosylceramide as a treatment for tuberculosis in patients with concurrent HIV infection. Our initial experiments have shown that treating mice with a-galactosylceramide, starting one day following intravenous inoculation with M. tuberculosis, prolongs their survival compared to administration of the vehicle alone. The main action of a-galactosylceramide is the activation of NKT cells in a CD1d dependent manner. The remarkable conservation of both CD1d and NKT cells in both humans and mice makes the mouse a suitable model to test the efficacy of a-galactosylceramide for the treatment of tuberculosis. The experiments proposed in Aim 1 will confirm and extend our finding that a-galactosylceramide protects mice from tuberculosis after inoculation with M. tuberculosis by both the intravenous and aerosol routes. An optimum dosing schedule will be developed and we will assess the efficacy of a-galactosylceramide in the treatment of established tuberculous disease. Additionally, changes in the tissue mycobacterial burden, histopathological features, and immunological parameters in treated and untreated mice will be examined to determine the manner in which a-galactosylceramide modifies the natural history of tuberculosis. In Aim 2, we will determine whether a-galactosylceramide acts synergistically with traditional anti-mycobacterial chemotherapy in the treatment of tuberculosis. We believe that this series of experiments will lay the foundation for the development of a-galactosylceramide as an adjunct therapy for tuberculosis, a treatment that ultimately may be relevant to other infectious diseases as well.